Cancer is a cellular malignancy whose unique trait, loss of normal control of cell cycle, results in unregulated growth, lack of differentiation, and ability to invade other tissues and metastasize. Carcinogenesis is a multi-step process by which a normal cell is transformed in a malignant cell (McKinnell et al., “The Biology Basis of Cancer”, Ch. 3, 1998). The etiology of cancer is complex and includes alteration of the cell cycle regulation, chromosomal abnormalities and chromosomes breakage. Infectious agents (e.g., oncogenic viruses), chemicals, radiation (e.g., ultraviolet or ionizing radiation) and immunological disorders are thought to be the major causes of carcinogenesis (McKinnell et al., “The Biological Basis of Cancer, Ch. 3, 1998).
Recent evidence supports the view that tumors are organized in a hierarchy of heterogeneous cell populations with different biological properties. Two models have been proposed to account for this heterogeneity within tumors and for tumor growth. One such model is based on cancer stem cells (CSCs) which are thought to be responsible for aspects of cancer such as initiation, progression, metastasis, and recurrence. See Chen et al., Acta Pharmacol Sin., 34(6):732-740, 2013; Ponti et al., Cancer Res, 65(13):5506-11, 2005; Singh et al., Cancer Res, 63:5821-5828, 2003; and Feng et al., Oncology Reports, 22:1129-1134, 2009. Although CSCs generally represent a very small population of the overall tumor population, they are generally regarded as a self-renewing initiation subpopulation of tumor cells or a small population of cancer cells that are capable of giving rise to new tumors. CSCs have been identified in a number of cancers including, but not limited to, breast, brain, blood, liver, kidney, cervical ovarian, colon, and lung cancers among others. See Ponti et al., Cancer Res, 65(13):5506-11, 2005; Feng et al., Oncology Reports, 22:1129-1134, 2009; Zhang et al., Cancer Res, 68(11):4311:4320, 2008: Singh et al., Cancer Res, 63:5821-5828, 2003; Clarke et al., Cancer Res, 66:9339, 2006; Sendurai et al., Cell, 133:704, 2008; Ohata et al., Cancer Res, 72:5101, 2012; and Mukhopapadhyay et al., Plos One, 8(11):e78725, 2013).
Surgical resection of tumor(s) or metastases arising from a primary tumor(s) followed by systemic administration of anti-cancer therapy is the established clinical protocol for treatment of several cancers. Although successful for treatment of some cancer types, a well-known complication of cancer treatment is the survival of residual tumor cells or CSCs that are not effectively removed which can result in relapse after remission, with the cancer returning at the primary site of tumor formation or at distant sites due to metastasis. Recently, it was found that CSCs may also contribute to relapse after remission due to resistance to chemotherapy. See Domingo-Domenech et al., Cancer Cell, 22(3):373, 2012. Therefore, there is a need for development of therapeutic agents that can target cells which contribute to relapse and metastasis (e.g., CSCs). Discovery of such therapeutic agents may allow for the development of treatment useful for preventing recurrence of cancer after remission (i.e., relapse) or preventing the spread of the primary tumour to secondary sites (i.e., metastasis). See Clarke et al., Cancer Res, 66:9339, 2006.
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